Our efforts in the past 22 years to study the chemistry and biology of nucleic acids in an integrated and comprehensive manner will be continued. This program has 4 sections: (1) The physico-chemical properties and interactions of nucleic acids will be studied by NMR on 1H, 13C, 31P, and 19F nuclei with the best spectrometer available. This project is made possible by the organic/biochemical synthesis of short helices, analogs, 13C or 19F labeled nucleic acid, etc., and by computer technology, with graphic facilities for improvement of NMR theory; (2) The structure and function of nucleic acids having specific, exposed/accessible sequences will be probed by appropriate nonionic oligonucleotide analogs (alkyl phosphotriesters or phosphonates, up to a decamer long) inside the living cells. These compounds form specific duplexes with complementary sequences, penetrate living cells, and resist enzyme degradation. Sequences in tRNA, mRNA, rRNA, and oncogenic viral RNA inside the living cells can be interacted with these analog probes, so that their functions can be analyzed, modified, and controlled; (3) DNA sequence organization and function of the mammalian genome (including human) will be investigated quantitatively, with emphasis on controlling sequences in gene expression, providing a basis for understanding (thereby possibly controlling) differentiation and neoplasia at the molecular level; (4) Interferon induction and the control process of interferon synthesis after induction will be investigated. The establishment of the temporal and structural requirements of double-stranded polynucleotide duplexes in acting as interferon inducers will aid in the isolation and characterization of the putative receptors for interferon induction. In a collaborative effort, the therapeutic value of mismatched polynucleotide duplexes synthesized in our laboratory will be tested in human viral disease by clinical trials. The control of interferon synthesis in the shut-off process will be elucidated in terms of molecular biology and somatic genetics as a model for the control of gene function. The above program is to be achieved with a team of 10 scientists, consisting of physical/NMR chemists, organic chemists, molecular biologists, cell biologists, and virologists.